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Anesth Analg 2003;96:532-538
© 2003 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Potent {sigma}1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine Provides Ischemic Neuroprotection Without Altering Dopamine Accumulation In Vivo in Rats

Toru Goyagi, MD*, Anish Bhardwaj, MD*,{dagger}, Raymond C. Koehler, PhD*, Richard J. Traystman, PhD*, Patricia D. Hurn, PhD*, and Jeffrey R. Kirsch, MD*,{dagger}

Departments of *Anesthesiology and Critical Care Medicine and {dagger}Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence and reprint requests to Anish Bhardwaj, MD, Neurosciences Critical Care Division, Meyer 8–140, Johns Hopkins Hospital, 600 N Wolfe St., Baltimore, MD 21287. Address e-mail to abhardwa{at}jhmi.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The in vivo signaling of ischemic neuroprotection provided by {varsigma}-receptor ligands remains unclear. Catecholamines have been implicated in the propagation of ischemic neuronal injury, and previous in vitro studies suggest that {varsigma} ligands modulate dopaminergic neurotransmission. In this study, we tested the hypothesis that the potent {varsigma}1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) attenuates the increase of extracellular dopamine in ischemic striatum. Under controlled physiological conditions, a microdialysis probe was implanted in right caudoputamen (CP) complex of adult male Wistar rats. Rats were subjected to 2 h of transient middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. In a blinded, randomized fashion, rats were divided into five treatment groups: Group 1 (n = 8; saline-saline) continuous IV infusion of saline vehicle 30 min before MCAO followed by saline at reperfusion until the end of the experiment; Group 2 (n = 8; PPBP-PPBP) IV PPBP 30 min before MCAO followed by 1 µmol · kg-1 · h-1 of PPBP; Group 3 (n = 8; saline-PPBP) IV saline before MCAO followed by PPBP; Group 4 (n = 4) surgical shams (saline-saline); and Group 5 (n = 4) surgical shams (PPBP-PPBP). Infarction volume at 22 h of reperfusion in the CP complex (percentage of ipsilateral structure) was significantly attenuated in rats treated with PPBP-PPBP (27.3% ± 9.1%) and saline-PPBP (27.8% ± 12.7%) compared with saline-saline (59.3% ± 7.3%) treatment. There was a three- to fourfold increase in dopamine concentrations in the microdialysates within 40 min of the onset of MCAO. Dopamine and its metabolites dihydroxy phenylacetic acid and homovallinic acid levels were similar among the three groups subjected to MCAO. Therefore, PPBP provides significant ischemic neuroprotection in the CP complex without altering the acute accumulation of dopamine in vivo during transient focal ischemia in the rat.

IMPLICATIONS: {varsigma}1-Receptor ligands decrease infarction size in the striatum when given before or after onset of stroke without affecting ischemia-evoked dopamine efflux.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Numerous studies have demonstrated robust neuroprotective properties of sigma ({varsigma})-receptor ligands in animal models of cerebral ischemia (1–6). We have demonstrated that the potent {varsigma}1-receptor ligand, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) attenuates infarction volume in a cat (5), rat (2,6,7), and mouse (8) after middle cerebral artery occlusion (MCAO). {varsigma} ligands interact with a number of neurotransmitter systems in the brain (9–11), and a variety of antiexcitotoxic mechanisms for {varsigma} ligands have been postulated that could account, in part, for the neuroprotective properties of this class of compounds. For example, {varsigma} ligands inhibit ischemia-induced presynaptic glutamate release (12), attenuate postsynaptic glutamate-evoked Ca2+ influx (13,14), modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation (15,16), inhibit dopaminergic neurotransmission (1), prevent cortical spreading depression (17), attenuate glutamate- and NMDA-induced nitric oxide (NO) synthase activation in vitro (15,18), and attenuate ischemia-evoked NO production in vivo (8).

Whereas the cascade of excitotoxic mechanisms during cerebral ischemia is complex, catecholamines likely play an important role in the propagation of brain injury after anoxia, hypoglycemia, and ischemia (19–23). For example, previous studies have demonstrated an increased susceptibility of dopaminergic nerve terminals to ischemic injury (24–26). Amelioration of histopathological injury after cerebral ischemia has been demonstrated after attenuation of ischemia-induced surges in extracellular dopamine (DA) by barbiturates (20) isoflurane and etomidate (27,28) and nigrostriatal lesioning (29). In vitro studies have demonstrated that {varsigma}-receptor ligands modulate DA release (1). Accordingly, in the present study, we used striatal microdialysis to test the hypothesis that PPBP provides neuroprotection by attenuating the acute release and accumulation of extracellular DA in the ischemic striatum after transient focal ischemia in the rat in vivo. Because extracellular DA may remain increased after reperfusion, we compared the effect of starting infusion of PPBP before ischemia with starting infusion at the onset of reperfusion.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental protocols were approved by the Institutional Animal Care and Use Committee and conform to the National Institutes of Health guidelines for the care and use of animals in research. All methods have been previously described in the rat (2,7,8,15,30).

Adult male Wistar rats (300–350 g; n = 38) were anesthetized with halothane (1%–2.0%) in oxygen-enriched air (35%–40%). Using aseptic surgical techniques, cannulae were inserted into the right femoral artery and vein to monitor mean arterial blood pressure (MABP), arterial blood gases, and for administration of fluids and drugs. After cannulation, both catheters were exteriorized in the posterior mid-thorax and fixed onto a swivel to allow for free movement of the rat in its cage after emergence from anesthesia. Physiological levels of arterial blood gases were maintained throughout the experiments; rectal temperatures were maintained at 38°C ± 0.5°C and temporalis muscle temperatures at 37°C ± 0.5°C with a heating lamp throughout the surgical procedures.

Dialysis probes used in these studies were constructed with a 3-mm length for effective dialysis, as previously described (8,31). After placement of arterial and venous catheters, a microdialysis cannula was stereotactically placed into the striatum (0.5 mm anterior and 2.5 mm lateral to the bregma; depth, 6 mm from the dura) and fixed in a position previously described (31). After a 60-min postsurgical equilibration period, microdialysis cannulae were perfused with artificial cerebrospinal fluid at 2 µL/min. Effluent dialysate samples of 40 µL were collected in 20 µL of 0.1 M of perchloric acid in Eppendorf vials over 20-min epochs for 1 h at baseline, 2 h of MCAO, and 3 h of reperfusion.

After implantation of the microdialysis cannulae and collection of baseline samples, rats were subjected to transient focal ischemia (120 min) by MCAO using an intraluminal filament technique, as previously described (30), with some modifications (2,7,8,15). Adequacy of MCAO and reperfusion was confirmed by laser Doppler flowmetry (LDF; Model MBF3D, Moor Instruments Ltd, Devon, England) over the ipsilateral parietal cortex. Rats that did not demonstrate a reduction of at least 40% of baseline signal during MCAO or rapid restoration of the LDF-signal during reperfusion were excluded from the study. LDF measurements were recorded at baseline, 15, 30, 60, 90, and 120 min after MCAO, immediately, and 5, 10, 30, 60, 120, 150, and 180 min of reperfusion. All surgical wounds were infiltrated with 0.25% bupivacaine. The rats were then allowed to awaken from anesthesia. After 180 min of reperfusion, the microdialysis probes were removed, and the scalp incision was sutured.

In a blinded, randomized fashion, rats were divided into five treatment groups: Group 1 (n = 8; saline-saline), continuous IV infusion of saline vehicle 30 min before MCAO followed by saline at reperfusion until the end of the experiment; Group 2 (n = 8; PPBP-PPBP), IV PPBP before MCAO followed by PPBP at reperfusion; Group 3 (n = 8; saline-PPBP), IV saline 30 min before MCAO followed by PPBP at reperfusion; Group 4 (n = 4), surgical shams (saline-saline); and Group 5 (n = 4), surgical shams (PPBP-PPBP). All IV infusions were at a rate of 0.5 mL/h. The dose of PPBP was 1 µmol · kg-1 · h-1.

At 3 h of reperfusion, rats were allowed to emerge from anesthesia in their individual cages and were given ad libitum access to food and water. At 22 h of reperfusion, rats were deeply anesthetized with 5% halothane and decapitated. The brain was harvested and sliced into seven 2-mm-thick coronal sections for staining with 1% triphenyltetrazolium chloride (TTC) in saline at 37°C for 30 min, as previously described (2,7,8,15). Infarction volume was measured using digital imaging (MTI Series 68 Video Camera, Dage-MTI, Michigan City, IN) and image analysis software (SigmaScan Pro, Jandel Scientific, San Rafael, CA). The infarcted area was numerically integrated across each section and over the entire ipsilateral hemisphere. Infarction volumes were measured separately in cerebral cortex and striatum and expressed as a percentage of the volume of the ipsilateral structure, as previously described (2,7,8,15). Microdialysis probe placement was confirmed within the area of TTC-determined infarction.

High-Performance Liquid Chromatography (HPLC) Measurements
Chromatographic conditions for measurement of monoamine neurotransmitters in microdialysates were performed using HPLC with electrochemical (EC) detection, as previously described (32). The HPLC system used a MD-150 (3 x 150 mm; 3 µm) column, a 10-µL injection loop, a Coluchem II 5200 EC-detector (ESA, Inc, Chelmsford, MA), and an analytical cell (Model 5014B), and the data was analyzed and stored on a computerized ESA 501 data system. The mobile phase (MD-TM; ESA Inc) consisted of acetonitrile, phosphate buffer, and an ion-pairing agent (ESA Inc). The detection limit of our system for DA was 2 nmol/L. Before and after each run, the uniformity and efficiency of chromatographic conditions was tested by injecting standard 10 µL of 0.05 µmol/L of DA and its metabolites 3,4,-dihydroxy phenylacetic acid (DOPAC) and homovallinic acid (HVA) in 0.1 M of perchloric acid. Isoproterenol was used as an internal standard.

DA, DOPAC, HVA, and isoproterenol were obtained from Sigma Chemicals (St Louis, MO). PPBP was a generous gift from National Institute for Drug Abuse (Bethesda, MD).

Overall significance levels of the cerebral microdialysis data were determined by analysis of variance (ANOVA). Simultaneous multiple comparisons were based on the least significant differences test. Infarction volumes were compared between groups by one-way ANOVA and Fisher’s least significance test. Physiological data between and within groups were analyzed by two-way ANOVA with Fisher’s post hoc test. A value of P < 0.05 was considered significant. Data are presented as means ± SEM.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
MCAO in Rats
MABP, PaCO2, PaO2, pH, and rectal and temporalis muscle temperatures were within normal physiological ranges in all groups before and during ischemia and on reperfusion (Table 1). Mortality before the end of the experimental protocol was 2 of 13 rats in Group 1, 1 of 9 rats in Group 2, and 1 of 5 rats in Group 5. Three rats were excluded from Group 1 because the intra-ischemic LDF did not decrease to 40% of baseline signal and did not remain less than this value during the period of MCAO. Thus, the numbers of rats that successfully completed the experimental protocol and included in the final data analyses were eight in Group 1, eight in Group 2, eight in Group 3, four in Group 4, and four in Group 5. Reduction of the LDF-flux signal during MCAO and reperfusion was not different among treatment groups. During MCAO, residual LDF signal was similar in all treatment groups (Group 1, 23% ± 3%; Group 2, 21% ± 3%; Group 3, 24% ± 4%). On withdrawal of the monofilament, the LDF signal returned rapidly to baseline values within 5 min in all treatment groups. Surgical shams (Groups 4 and 5) did not have any alteration in LDF signal. The TTC-determined infarction volume (percentage of ipsilateral structure) was significantly attenuated in the caudoputamen complex in rats treated with PPBP-PPBP (27.3% ± 9.1%) and saline-PPBP (27.8% ± 12.7%) compared with the saline-saline (59.3% ± 7.3%) treatment (Fig. 1).


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  		Table 1. Summary of Selected Physiological Variables at Baseline (preischemia), During Ischemia, and 90 min of Reperfusion (reperfusion) in Treatment Groups Exposed to Saline-Saline (n = 8), Saline-PPBP (n = 8), PPBP-PPBP (n = 8), Sham Saline-Saline (n = 4), and Sham PPBP-PPBP (n = 4)
 


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  		Figure 1. Triphenyltetrazolium chloride-determined infarction volume at 22 h of reperfusion in rats after 2 h of middle cerebral artery occlusion in the caudoputamen (CP) complex in rats treated with saline-saline (controls; n = 8), 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP)-PPBP (1 µmol · kg-1 · h-1) (n = 8), and saline-PPBP (n = 8). *P < 0.05 versus saline-saline treated control rats.

 
Microdialysis
In vitro recovery of microdialysis probes for DA at 2 µL/min is approximately 3%. There was a marked increase (three- to fourfold) in striatal DA concentrations from preischemic values in the first microdialysate collection sample in all treatment groups that were subjected to MCAO (Fig. 2). The increase in DA was not attenuated by pretreatment with PPBP. These values gradually returned to preischemic baseline values at reperfusion. Neither pretreatment nor posttreatment altered DA concentrations in the dialysates during reperfusion. Surgical shams did not demonstrate an increase in extracellular DA. In the three treatment groups subjected to MCAO, DOPAC and HVA dialysate levels decreased significantly at the onset of ischemia and returned to preischemic baseline values at the onset of reperfusion (Fig. 3). There were no changes in extracellular DA, DOPAC, and HVA dialysate levels in surgical shams.



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  		Figure 2. Line graphs depicts extracellular dopamine (DA) concentrations (µmol/L) in the striatum of rats at baseline, middle cerebral artery occlusion (MCAO), and reperfusion in rats treated with saline-saline (controls; n = 8), 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP)-PPBP (1 µmol · kg-1 · h-1) (n = 8), saline-PPBP (n = 8), and surgical shams treated with saline-saline (n = 4) or PPBP-PPBP (n = 4). DA concentrations during MCAO (20 min through 120 min) are significantly different from preischemic baseline values.

 


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  		Figure 3. (A) Line graph depicts extracellular concentrations of dihydroxy phenylacetic acid (DOPAC; µmol/L) at baseline, middle cerebral artery occlusion (MCAO), and reperfusion in rats treated with saline-saline (controls; n = 8), 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP)-PPBP (1 µmol · kg-1 · h-1) (n = 8), saline-PPBP (n = 8), and surgical shams treated with saline-saline (n = 4) or PPBP-PPBP (n = 4). DOPAC concentrations during MCAO (20 min through 120 min) are significantly different from preischemic baseline values. (B) Line graph depicts extracellular concentrations of homovallinic acid (HVA; µmol/L) at baseline, MCAO, and reperfusion in rats treated with saline-saline (controls; n = 8), PPBP-PPBP (1 µmol · kg-1 · h-1) (n = 8), saline-PPBP (n = 8), and surgical shams treated with saline-saline (n = 4) or PPBP-PPBP (n = 5). DOPAC concentrations during MCAO (20 min through 120 min) are significantly different from preischemic baseline values.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The significant findings of this study are that the prototypic {varsigma}1-receptor ligand PPBP confers robust ischemic neuroprotection from transient focal ischemia without altering acute release and accumulation of extracellular DA in the ischemic core of the striatum. The results of the present study confirm our previous findings that the {varsigma}1-ligand prototype PPBP provides consistent histologic neuroprotection after transient focal cerebral ischemia (2,6,7). Although previous work in vitro suggested that these compounds might decrease catecholamine release, we now show that this mechanism is not apparent in the ischemic core in the striatum in vivo. Our study cannot exclude the possibility that PPBP decreases infarct size by altering catecholamine release in the ischemic penumbra.

Widespread and heterogeneous labeling of {varsigma}-receptors has been demonstrated in the brain (33), and these receptors seem to interact with a variety of neurotransmitter systems. For example, binding studies have demonstrated that norepinephrine (NE) or serotonin uptake inhibitors potently block [3H](+)-3-PPP binding to {varsigma}-receptors in the rat brain (9). {varsigma}-Receptors also interact with DA neurotransmission, and these responses seem to be region specific. For example, (+)-pentazocine increases the activity of DA neurons in the ventral tegmental area (A10) but decreases the activity of neurons in the substantia nigra pars compacta (A9) (11). Another selective {varsigma}-receptor antagonist, SKF-10,047, and progesterone, a putative endogenous {varsigma}-receptor ligand, produce increased dopamine uptake in the rat nucleus accumbens (34). Another selective {varsigma}-receptor ligand, MS-377, reverses phencyclidine-induced release of dopamine and serotonin in the rat cortex (35). Using in vivo microdialysis, we have shown that local PPBP administration via microdialysis infusate into striatum can rapidly suppress NMDA-induced conversion of arginine to citrulline (as an indirect measure of NO synthase activity) in the microdialysis effluent (15). Furthermore, PPBP attenuates ischemia-evoked striatal NO production (8).

Acute release of catecholamines (DA and NE) has been demonstrated after cerebral ischemia (19–21,29,36) and has been implicated in the pathogenesis and propagation of ischemic neuronal injury. Several experimental studies suggest that catecholamine release and metabolism may underlie the selective vulnerability of striatal neurons to an ischemic insult (25,26,37). Depletion of catecholamine stores by {alpha}-methyl-para-tyrosine exerts a strong protective effect on ischemic damage to nerve terminals (25). Micromolar concentrations of DA and NE are toxic to metabolic enzymes in brain homogenates (38). Unilateral nigrotomy, which reduces striatal DA content by lesioning the nigrostriatal tract, protects intrinsic striatal neurons from injury after global cerebral ischemia (29). Whereas the precise mechanism of neuronal injury by DA is unclear, bi-products of its metabolism such as hydrogen peroxide, superoxide ion, and hydrogen radicals have been implicated in this deleterious process (39). In our study, there was an acute large increase in DA in the first 20-minute microdialysis sample after the onset of MCAO. However, pretreatment with PPBP did not attenuate DA levels as compared with saline-treated controls.

We did not observe a secondary increase in DA levels during reperfusion. The metabolism of DA proceeds predominantly via cytosolic neuronal reuptake and subsequent conversion to DOPAC by monoamine oxidase (27,40). DOPAC is then converted to HVA by the membrane-bound catechol-O-methyltransferase. Consistent with previous reports (27,40), DOPAC and HVA were decreased during MCAO in the three treatment groups subjected to transient focal ischemia in our study. The fact that we did not observe increased extracellular concentrations of these metabolites accompanying increased extracellular DA suggests that ischemia-induced DA release is not rapidly metabolized, presumably because of either impaired DA reuptake mechanisms, ischemia-induced metabolic enzyme failure, or membrane potential-dependent active transport system failure (40). However, previous studies have demonstrated increased whole tissue levels of DOPAC and HVA for up to seven hours after experimental stroke (26). Furthermore, additional evidence for continued DA metabolism is that DA terminals isolated from the ischemic brain can actively take up DA in vitro for up to eight hours after ischemia (26). Thus, reduced levels of DA and DOPAC during isch-emia in the extracellular space suggest that these metabolites may be intracellularly formed, and only restricted amounts enter the extracellular space (19,20,40). During reperfusion, there was a gradual return of DOPAC and HVA to preischemic baseline values, suggesting a recovery of reuptake and enzymatic function. Biphasic effects of {varsigma}-receptor ligands on extracellular concentrations of striatal DA have been reported, suggesting that DA release may be modulated by multiple {varsigma}-receptor subtypes (41). It has been suggested that {varsigma}1-binding sites selectively interact with the NMDA receptor channel complex on the DA nerve terminals, thereby modulating DA release (41,42).

In this series of experiments, the 3-mm tips of the microdialysis probes that constitute the active region of dialysis (31,43) were localized in the striatum as confirmed by postmortem brain dissection. We did not localize the probe position in the anatomical subdivisions of the striatum (putamen or the caudate). We chose the striatum as the region of study because (a) it is consistently an injured region after MCAO in our model, (b) our previous studies have demonstrated significant and consistent ischemic neuroprotection in the striatum after transient focal ischemia in the rat, and (c) it is well established that the striatum is highly vulnerable to cerebral ischemia (44). Neurochemical sampling is from brain regions in close vicinity to the microdialysis probe. Previous studies have demonstrated that there is a direct linear relationship between concentrations of endogenous substances in the medium surrounding the microdialysis probe and the substance recovered in the dialysate (45). Thus, relative increases in concentrations of DA and its metabolites were estimated accurately by HPLC in our study. However, absolute values may have been underestimated because of limitations of the microdialysis technique. There was some inter-animal variability in neurochemical values that may have arisen from physiological factors such as MABP, blood gases, and depth of anesthesia, although there were no significant differences in these variables in different treatment groups. Differences in the absolute levels of DA and its metabolites are evident between different groups receiving similar interventions. Some of this variability may be due to the severity of ischemia. For example, portions of striatum supplied by the anterior cerebral artery are subjected to less severe ischemia, and the volume of tissue subtended by the microdialysis probe may include this less severely ischemic region in some animals. Variability may also arise from tissue injury resulting from placement of a 300-µm-diameter probe.

In conclusion, PPBP confers ischemic neuroprotection but not by a mechanism involving reduction of DA release during ischemic-anoxic depolarization.


   Acknowledgments
 
This work was supported in part by United States Public Health Service National Institutes of Health grant NS20020 and NS33668. A. Bhardwaj is supported in part by an Established Investigator Grant from the American Heart Association.

The authors thank Edythe D. London for providing the {varsigma}1-receptor ligand PPBP used in this study.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication October 2, 2002.




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